The present invention relates to hetero-tetrahydroquinolines, to processes for their preparation and to their use in medicaments.
The publication US-5 169 857-A2 discloses 7-(polysubstituted pyridyl)-6-heptenoates for treating arteriosclerosis, lipoproteinaemia and hyperproteinaemia. Moreover, the preparation of 7-(4-aryl-3-pyridyl)-3,5-dihydroxy-6-heptenoates is described in the publication EP-325 130-A2. Furthermore, the compound 5(6H)-quinolone, 3-benzyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl is known from the publication Khim. Geterotsikl. Soedin. (1967), (6), 1118-1120.
The present invention relates to hetero-tetrahydroquinolines of the general formula (I) 
in which
A represents cycloalkyl having 3 to 8 carbon atoms or
represents a 5- to 7-membered saturated, partially unsaturated or unsaturated, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and O which, in the case of a saturated heterocycle with a nitrogen function, is optionally also attached via this function, and where the abovementioned ring systems are optionally substituted up to 5 times by identical or different substituents from the group consisting of halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy having in each case up to 7 carbon atoms, or by a group of the formula xe2x80x94NR3R4, in which
R3 and R4 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, or
A represents a radical of the formula 
D represents aryl having 6 to 10 carbon atoms which is optionally substituted by phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or
represents a radical of the formula 
xe2x80x83in which
R5, R6 and R9 independently of one another represent cycloalkyl having 3 to 6 carbon atoms, or
xe2x80x83represent aryl having 6 to 10 carbon atoms or represent a 5- to 7-membered optionally benzo-fused saturated or unsaturated mono-, bi- or tricyclic hetreocycle having up to 4 heteroatoms from the group consisting of S, N and O,
xe2x80x83where the cycles are optionally substituted, in the case of the nitrogen-containing rings also via the N function, up to 5 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, and straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryl having in each case 6 to 10 carbon atoms or by an optionally benzo-fused aromatic 5- to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and O,
xe2x80x83and/or by a group of the formula xe2x80x94OR10, xe2x80x94SR11, xe2x80x94SO2R12 or xe2x80x94NR13R14, in which
R10, R11 and R12 independently of one another represent aryl having 6 to 10 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, halogen and straight-chain or branched alkyl having up to 6 carbon atoms,
R13 and R14 are identical or different and have the meaning of R3 and R4 given above, or
R5 and/or R6 represent(s) a radical of the formula 
R7 represents hydrogen or halogen, and
R8 represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 6 carbon atoms or a radical of the formula xe2x80x94NR15R6, in which
R15 and R16 are identical or different and have the meaning of R3 and R4 given above, or
R7 and R8 together form a radical of the formula xe2x95x90O or xe2x95x90NR17, in which
R17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 6 carbon atoms,
L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 8 carbon atoms which are optionally substituted up to 2 times by hydroxyl,
T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 8 carbon atoms, or
T or X represents a bond,
V represents an oxygen or sulphur atom or represents an xe2x80x94NR18 group, in which
R18 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
E represents cycloalkyl having 3 to 8 carbon atoms, or
represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents phenyl which is optionally substituted by halogen or trifluoromethyl,
R1 and R2 together form a straight-chain or branched alkylene chain having up to 7 carbon atoms which has to be substituted by a carbonyl group and/or by a radical of the formula 
xe2x80x83in which
a and b are identical or different and represent a number 1, 2 or 3,
R19 represents hydrogen, cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched silylalkyl having up to 8 carbon atoms or straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or by phenyl which for its part may be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or tetrazole-substituted phenyl,
xe2x80x83and alkyl is optionally substituted by a group of the formula xe2x80x94OR22, in which
R22 represents straight-chain or branched acyl having up to 4 carbon atoms or benzyl, or
R19 represents straight-chain or branched acyl having up to 20 carbon atoms or benzoyl which is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or
xe2x80x83represents straight-chain or branched fluoroacyl having up to 8 carbon atoms and 9 fluorine atoms,
R20 and R21 are identical or different, represent hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, or
R20 and R21 together form a 3 to 6-membered carbocycle
xe2x80x83and, if appropriate also geminally, the carbocycles formed are optionally substituted up to 6 times by identical or different substituents from the group consisting of trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy having in each case 3 to 7 carbon atoms, straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio having in each case up to 6 carbon atoms and straight-chain or branched alkyl having up to 6 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl or carboxyl having in each case up to 4 carbon atoms and phenyl which for its part may be substituted by halogen, trifluoromethyl or trifluoromethoxy,
xe2x80x83and/or the carbocycles formed are optionally substituted, also geminally, up to 5 times by identical or different substituents from the group consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their part are optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro,
xe2x80x83and/or are optionally substituted by a radical of the formula 
xe2x80x83in which
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R23 and R24 are identical or different and represent hydrogen, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl which is optionally substituted up to 2 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, cyano, phenyl and nitro,
xe2x80x83and/or the carbocycles formed are optionally substituted by a spiro-linked radical of the formula 
xe2x80x83in which
W represents either an oxygen or a sulphur atom,
Y and Yxe2x80x2 together form a 2- to 6-membered straight-chain or branched alkylene chain,
e represents a number 1, 2, 3, 4, 5, 6 or 7,
f represents a number 1 or 2,
R25, R26, R27, R28, R29, R30 and R31 are identical or different and represent hydrogen, trifluoromethyl, phenyl, halogen or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, or
R25 and R26 or R27 and R28in each case together form a straight-chain or branched alkyl chain having up to 6 carbon atoms, or
R25and R26 or R27 and R28 in each case together form a radical of the formula 
xe2x80x83in which
W is as defined above,
g represents a number 1, 2, 3, 4, 5, 6 or 7,
R32 and R33 together form a 3- to 7-membered heterocycle which contains an oxygen or sulphur atom or a group of the formula SO, SO2 or xe2x80x94NR34, in which
R34 represents hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,
and their salts and N-oxides.
The hetero-tetrahydroquinolines according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, preference is given to physiologically acceptable salts. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particular preference is given, for example, to sodium salts, potassium salts, magnesium salts or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds according to the invention can exist in stereoisomeric forms which are either like image and mirror image (enantiomers), or which are not like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform components in a known manner.
In the context of the invention, a 3- to 8-membered saturated carbocyclic ring represents a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ring. Preference is given to a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. Particular preference is given to cyclobutyl, cyclopentyl or cyclohexyl.
In the context of the invention, heterocycle generally represents a saturated, partially unsaturated or unsaturated, optionally benzo-fused 5- to 7-membered, preferably 5- to 6-membered, heterocycle which may contain up to 3 heteroatoms from the group consisting of S, N and O. Examples which may be mentioned are: indolyl, isoquinolyl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Preference is given to quinolyl, furyl, pyridyl and thienyl.
Preference is given to the compounds of the general formula (I) according to the invention, in which
A represents cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl or cyclohexyl, or
represents thienyl, imidazolyl, pyrrole, furyl, pyridyl, morpholine, pyrimidyl or pyridazinyl, which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or branched alkyl, and alkoxy having in each case up to 6 carbon atoms, or
A represents a radical of the formula 
D represents phenyl which is optionally substituted by nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or trifluoromethoxy, or
xe2x80x83represents a radical of the formula 
xe2x80x83in which
R5, R6 and R9 independently of one another represent cyclopropyl, cyclopentyl or cyclohexyl, or
xe2x80x83represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl,
xe2x80x83where the cycles are optionally substituted up to 3 times, in the case of the nitrogen-containing rings also via the N function, by identical or different substituents from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl, trifluoromethyl-substituted phenyl and phenyl, or
R7 represents hydrogen, fluorine, chlorine or bromine, and
R8 represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 5 carbon atoms or a radical of the formula xe2x80x94NR15R16,
xe2x80x83in which
R15 and R16 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, or
R7 and R8 together form a radical of the formula xe2x95x90O or xe2x95x90NR17, in which
R17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms,
L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 6 carbon atoms which are optionally substituted up to 2 times by hydroxyl,
T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 6 carbon atoms, or
T or X represents a bond,
V represents an oxygen or sulphur atom or represents a group of the formula xe2x80x94NR18xe2x80x94,
xe2x80x83in which
R18 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by cyclopropyl, -butyl, -hexyl, -pentyl, -heptyl or by hydroxyl, or represents phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl,
R1 and R2 together form a straight-chain or branched alkylene chain having up to 6 carbon atoms which has to be substituted by a carboxyl group and/or by a radical of the formula 
xe2x80x83in which
a and b are identical or different and represent a number 1, 2 or 3,
R19 represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms or by phenyl which for its part may be substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or tetrazole-substituted phenyl,
and alkyl is optionally substituted by a group of the formula xe2x80x94OR22,
xe2x80x83in which
R22 represents straight-chain or branched acyl having up to 3 carbon atoms or benzyl,or
R19 represents straight-chain or branched acyl having up to 18 carbon atoms or benzoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or represents straight-chain or branched fluoroacyl having up to 6 carbon atoms,
R20 and R21 are identical or different, represent hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, or
R20 and R21 together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring,
xe2x80x83and the carbocycles formed are optionally substituted, if appropriate, also geminally, up to 5 times by identical or different substituents from the group consisting of trifluoromethyl, hydroxyl, carboxyl, azido, fluorine, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio having in each case up to about 5 carbon atoms and straight-chain or branched alkyl having up to 5 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of hydroxyl, benzyloxy, benzoyl, straight-chain or branched alkoxy or oxyacyl having in each case up to 3 carbon atoms, trifluoromethyl and phenyl which for its part may be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
xe2x80x83and/or the carbocycles formed are optionally substituted, also seminally, up to 4 times by identical or different substituents from the group consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their part are optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or nitro,
xe2x80x83and/or are optionally substituted by a radical of the formula 
xe2x80x83in which
c represents a number 1, 2, 3 or 4,
d represents a number 0 or 1,
R23 and R24 are identical or different and represent hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, straight-chain or branched alkyl having up to 5 carbon atoms, benzyl or phenyl which is optionally substituted by fluorine, chlorine, bromine, phenyl or trifluoromethyl,
and/or the carbocycles formed are optionally substituted by a spiro-linked radical of the formula 
xe2x80x83in which
W represents either an oxygen or a sulphur atom,
Y and Yxe2x80x2 together form a 2- to 5-membered straight-chain or branched alkyl chain,
e represents a number 1, 2, 3, 4, 5 or 6,
f represents a number 1 or 2,
R25, R26, R27 and R28 are identical or different and represent hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or
R25 and or R27 and R28 in each case together form a straight-chain or branched alkyl chain having up to 5 carbon atoms or
R25 and R26 or R27 and R28 in each case together form a radical of the formula 
xe2x80x83in which
W is as defined above,
g represents a number 1, 2, 3, 4, 5 or 6,
and their salts and N-oxides.
Particular preference is given to compounds of the general formula (I) according to the invention, in which
A represents cyclopropyl, cyclopentyl or cyclohexyl, or
represents thienyl or pyridyl which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or
A represents a radical of the formula 
D represents phenyl which is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or
represents a radical of the formula 
xe2x80x83in which
R5, R6 and R9 independently of one another represent cyclopropyl, cyclopentyl or cyclohexyl, or
represent phenyl, naphthyl or pyridyl,
where the cycles optionally up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy and straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or
R7 represents hydrogen or fluorine, and
R8 represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl having in each case up to 4 carbon atoms or a radical of the formula xe2x80x94NR15R16,
xe2x80x83in which
R15 and R16 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or
R7 and R8 together represent a radical of the formula xe2x95x90O,
L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms which are optionally substituted up to 2 times by hydroxyl,
T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or
T or X represents a bond,
V represents an oxygen or sulphur atom or a group of the formula xe2x80x94NR18, in which
R18 represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluorine or trifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl,
R1 and R2 together form a straight-chain or branched alkylene chain having up to 5 carbon atoms which has to be substituted by a carbonyl group and/or a radical of the formula xe2x80x94OR19,
xe2x80x83in which
R19 represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or
R19 represents straight-chain or branched acyl having up to 15 carbon atoms or benzoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or
xe2x80x83represents a radical of the formula xe2x80x94Si(CH3)2C(CH3)3,
xe2x80x83and the carbocycles formed are optionally substituted, if appropriate also geminally, up to 4 times by identical or different substituents from the group consisting of fluorine, hydroxyl, trifluoromethyl, carboxyl, azido, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio having in each case up to 4 carbon atoms and straight-chain or branched alkyl having up to 4 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of hydroxyl, benzyloxy, trifluoromethyl, benzoyl, methoxy, oxyacetyl and phenyl which for its part may be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
xe2x80x83and/or the carbocycles formed are optionally substituted, also geminally, up to 4 times by identical or different substituents from the group consisting of phenyl, benzoyl, thiophenyl and sulphonylbenzyl which for their part are optionally substituted by fluorine, trifluoromethyl, trifluoromethoxy or nitro, and/or are optionally substituted by a radical of the formula 
xe2x80x83in which
c represents a number 1, 2, 3 or 4,
xe2x80x83and/or the carbocycles formed are optionally substituted by a spiro-linked radical of the formula 
xe2x80x83in which
e represents a number 1, 2, 3, 4 or 5,
R25, R26, R27 and R28 are identical or different and represent hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, or
R25 and R26 or R27 and R28 together form a straight-chain or branched alkyl chain having up to 4 carbon atoms,
and their salts and N-oxides.
Very particular preference is given to compounds of the general formula (I) according to the invention, in which
A represents cyclopropyl, cyclopentyl or cyclohexyl, or
represents thienyl or pyridyl, or A represents a radical of the formula 
D represents phenyl which is optionally substituted by trifluoromethyl, fluorine, or
represents a radical of the formula 
xe2x80x83in which
R6 represents phenyl which is optionally substituted by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl having in each case up to 4 carbon atoms, or
R7 represents hydrogen or fluorine, and
R8 represents hydrogen, fluorine, chlorine, hydroxyl, methoxy or
R7 and R8 together represent a radical of the formula xe2x95x90O,
E represents cyclopropyl, cyclopentyl or cyclohexyl
represents straight-chain or branched alkyl having up to 4 carbon atoms,
R1 and R2 together form a straight-chain or branched alkylene chain having up to 5 carbon atoms which has to be substituted by a carbonyl group and/or a radical of the formula xe2x80x94OR19,
in which
R19 represents hydrogen
or represents a radical of the formula xe2x80x94Si(CH3)2C(CH3)3,
and their salts and N-oxides.
Moreover, processes for preparing the compounds of the general formula (I) according to the invention have been found, characterized in that
[A] in the case where Dxe2x89xa0aryl, compounds of the general formula (II) 
xe2x80x83in which
A, E, R1 and R2 are as defined above,
with organometallic reagents in a Grignard or Wittig reaction or in a reaction with organolithium compounds, the substituent D is synthesized in inert solvents,
or in the case where D represents the radical of the formula R9xe2x80x94Txe2x80x94Vxe2x80x94X in which V is an oxygen atom,
[B] either compounds of the general formula (III) 
xe2x80x83in which
A, E, X, R1 and R2 are as defined above,
are reacted with compounds of the general formula (IV)
R9xe2x80x94Txe2x80x94Zxe2x80x83xe2x80x83(IV),
xe2x80x83in which
R9 and T are as defined above and
Z represents halogen, preferably chlorine or bromine, in inert solvents, if appropriate in the presence of a base and/or auxiliary, or
[C] compounds of the general formula (III) are initially, by reaction with compounds of the general formula (V) 
xe2x80x83in which
R35 represents straight-chain alkyl having up to 4 carbon atoms, converted into the compounds of the general formula (VI) 
xe2x80x83in which
A, E, X, R1, R2 and R35 are as defined above, and subsequently reacted with compounds of the general formula (VII)
R9xe2x80x94Txe2x80x94Vxe2x80x94H (VII),
xe2x80x83in which
R9, T and V are as defined above,
and, if appropriate, protective groups are removed, or
[D] in the case of the compounds of the general formula (Ia) 
xe2x80x83in which
A and R6 are as defined above,
R36 and R37 are identical or different and
represent cycloalkyl or cycloalkyloxy having in each case 3 to 7 carbon atoms, or
represent straight-chain or branched alkyl having up to 6 carbon atoms, or represent phenyl which for its part are optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro, or
R36 and R37 represent one of the abovementioned spiro-linked radicals of the formula 
xe2x80x83in which
W, Y, Yxe2x80x2, R25, R26 R27, R28, e, R29 R30, R31 , R32 and R33 are as defined above,
compounds of the general formula (VIII) 
xe2x80x83in which
R6, R36, R37, A and E are as defined above,
are initially oxidized to the compounds of the general formula (IX) 
xe2x80x83in which
R6, R36, R37, A and E are as defined above,
these are, in a subsequent step, converted by asymmetric reduction into the compounds of the general formula (X) 
xe2x80x83in which
R6, R36 , R37, A and E are as defined above,
these are then converted, by the introduction of a hydroxyl protective group, into the compounds of the general formula (XI) 
xe2x80x83in which
R6, R36, R37, A and E are as defined above and
R38 represents a hydroxyl protective group, preferably a radical of the formula xe2x80x94SiR39R40R41, in which
R39, R40 and R41 are identical or different and represent C1-C4-alkyl,
which is used to prepare in a subsequent step, by diastereoselective reduction, the compounds of the general formula (XII) 
xe2x80x83in which
R6, R36, R37, R38, A and E are as defined above,
and the compounds of the general formula (XIII) 
xe2x80x83in which
R6, R36, R37, R38, A and E are as defined above,
are subsequently prepared by introducing the fluorine substituent with fluorinating agents, such as, for example, DAST and SF4 derivatives,
and the hydroxyl protective group is then removed by customary methods,
and, if appropriate, the substituents listed under D, E and/or R1 and R2 are varied or introduced by customary methods.
By way of example, the processes according to the invention can be illustrated by the following schemes: 
Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane.
Suitable bases for the individual steps are the customary strongly basic compounds. These preferably include organolithium compounds such as, for example, N-butyllithium, sec-butyllithium, tertbutyllithium or phenyllithium, or amides such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopropylamide.
Suitable for the processes [B] and [C] are furthermore the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium bicarbonate. Particular preference is given to using sodium hydride or potassium hydroxide.
Suitable organometallic reagents are, for example, systems such as Mg/bromobenzotrifluoride and p-trifluoromethylphenyllithium.
The reductions are generally carried out with reducing agents, preferably those which are suitable for reducing ketones to hydroxyl compounds are. Particularly suitable for this purpose is the reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out using complex metal hydrides such as, for example, lithium borohydrides, sodium borohydrides, potassium borohydrides, zinc borohydrides, lithium trialkylborohydride, diisobutylaluminium hydride or lithium aluminium hydride. The reaction is very particularly preferably carried out using diisobutylaluminium hydride and sodium borohydride.
The reducing agent is generally employed in an amount of from 1 mol to 6 mol, preferably from 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
The reduction generally proceeds in a temperature range of from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably of from xe2x88x9278xc2x0 C. to 0xc2x0 C. in the case of DIBAH, of from 0xc2x0 C. to room temperature in the case of NaBH4, particularly preferably at xe2x88x9278xc2x0 C., in each case depending on the choice of reducing agent and solvent.
The reduction generally proceeds at atmospheric pressure; however, it is also possible to carry out the reduction at elevated or reduced pressure.
In the case [A], the process is preferably carried out using initially compounds of the general formula (II) in which the carbocycle R1/R2 is initially only substituted by a group xe2x80x94OSiRIRIIRIII in which RI, RII and RIII are identical or different and represent phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, and the substituent mentioned above under R19/R20 is introduced by customary methods after the protective group has been removed.
Removal of the protective group is generally carried out in one of the abovementioned alcohols and THF, preferably methanol/THF, in the presence of hydrochloric acid in a temperature range of from 0xc2x0 C. to 50xc2x0 C., preferably at room temperature, and at atmospheric pressure. In particular cases, preference is given to removing the protective group with tetrabutylammonium fluoride (TBAF) in THF.
In the context of the definition given above, hydroxyl protective group generally represents a protective group from the group trimethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, tert-butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, tetrahydropyranyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, methoxyethoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxybenzoyl. Preference is given to tetrahydropyranyl, tertbutyldimethylsilyl and triisopropylsilyl. Particular preference is given to tertbutyldimethylsilyl.
Suitable solvents for the individual steps are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, diisopropyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene. It is also possible to use mixtures of the solvents mentioned.
Suitable oxidizing agents for preparing the compounds of the general formula (IX) are, for example, nitric acid, cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic alumina, osmium tetroxide and manganese dioxide. Preference is given to manganese dioxide and nitric acid.
The oxidation is carried out in one of the abovementioned chlorinated hydrocarbons and water. Preference is given to dichloromethane and water.
The oxidizing agent is employed in an amount of from 1 mol to 10 mol, preferably from 2 mol to 5 mol, based on I mol of the compounds of the general formula (VIII).
The oxidation generally proceeds at a temperature of from xe2x88x9250xc2x0 C. to +100xc2x0 C., preferably from 0xc2x0 C. to room temperature.
The oxidation generally proceeds at atmospheric pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.
The asymmetric reduction to the compounds of the general formula (X) is generally carried out in one of the abovementioned ethers or toluene, preferably tetrahydrofuran and toluene.
The reduction is generally carried out using enantiomerically pure 1R,2S-aminoindanol and borane complexes such as BH3xc3x97THF, BH3xc3x97DMS and BH3xc3x97(C2H5)2NC6H5. Preference is given to the system borane-diethylaniline/1R,2S-aminoindanol.
The reducing agent is generally employed in an amount of from 1 mol to 6 mol, preferably from 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
The reduction generally proceeds at a temperature of from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably from 0xc2x0 C. to 30xc2x0 C.
The reduction generally proceeds at atmospheric pressure; however, it is also possible to carry out the reduction at elevated or reduced pressure.
The hydroxyl protective group is introduced in one of the abovementioned hydrocarbons, dimethylformamide or THF, preferably in toluene in the presence of lutidine in a temperature range of from xe2x88x9220xc2x0 C. to +50xc2x0 C., preferably from xe2x88x925xc2x0 C. to room temperature and at atmospheric pressure.
General reagents for introducing the silyl protective group are tert-butyldimethylsilyl chloride or tert-butyldimethylsilyl trifluoromethanesulphonate. Preference is given to tert-butyldimethylsilyl trifluoromethanesulphonate.
The reduction to the compounds of the general formula (XII) proceeds in one of the abovementioned hydrocarbons, preferably toluene.
The reduction to prepare the compounds of the general formula (XII) is generally carried out using customary reducing agents, preferably those which are suitable for reducing ketones to hydroxyl compounds. Particularly suitable for this purpose is the reduction with metal hydrides or complex metal hydrides in the abovementioned inert solvents, such as, for example, toluene, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out using complex metal hydrides such as, for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride, diisobutylaluminium hydride, sodium bis-(2-methoxyethoxy)aluminium hydride or lithium aluminium hydride. The reduction is very particularly preferably carried out using sodium bis-(2-methoxyethoxy)aluminium hydride.
The reducing agent is generally employed in an amount of from 1 mol to 6 mol, preferably from 1 mol to 3 mol, based on 1 mol of the compounds to be reduced.
The reduction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to +110xc2x0 C., preferably from 0xc2x0 C. to room temperature.
The reduction generally proceeds at atmospheric pressure; however, it is also possible to carry out the reduction at elevated or reduced pressure.
In the reduction to the compounds of the general formula (XII), small residues of the wrong diastereomer remain in the mother liquor. These residues can be reoxidized with customary oxidizing agents such as, for example, pyridinium chlorochromate (PCC) or activated manganese dioxide, in particular with activated manganese dioxide, to give protected (XI) and thus be recycled into the synthesis cycle without any loss in yield.
The fluorine substituent is generally introduced in one of the abovementioned hydrocarbons or methylene chloride, preferably in toluene and under an atmosphere of protective gas.
Under SF4 derivatives, in general diethylamino sulphur trifluoride or 2,2xe2x80x2-bisfluoro-substituted amines such as, for example, diethyl-1,2,3,3,3-hexafluoropropylamine are prepared.
The reaction generally proceeds at a temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., in the case of dimethylamino sulphur trifluoride preferably at from xe2x88x9278xc2x0 C. to RT and in the case of diethyl-1,1,2,3,3,3-hexafluoropropylamine preferably at from room temperature to 80xc2x0 C.
The protective group is generally removed in one of the abovementioned alcohols and THF, preferably methanol/THF in the presence of hydrochloric acid in a temperature range of from 0xc2x0 C. to 50xc2x0 C., preferably at room temperature, and atmospheric pressure. In particular cases, preference is given to removing the protective group with tetrabutylammonium fluoride (TBAF) in THF at room temperature.
The following types of reaction may be mentioned by way of example for derivatizations:
oxidations, reductions, hydrogenations, halogenation, Wittig/Grignard reactions and amidations/sulphoamidations.
Suitable bases for the individual steps are the customary strongly basic compounds. These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyllithium, tertbutyllithium or phenyllithium, or amides such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopropylamide.
Suitable bases are furthermore the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium bicarbonate. Particular preference is given to using sodium hydroxide or potassium hydroxide.
Suitable solvents for the individual reaction steps are also alcohols such as methanol, ethanol, propanol, butanol or tertbutanol. Preference is given to tertbutanol.
If required, it may be necessary to carry out some reaction steps under an atmosphere of protective gas.
The halogenations are generally carried out in one of the abovementioned chlorinated hydrocarbons, preference being given to methylene chloride.
Suitable halogenating agents are, for example, diethylamino sulphur trifluoride (DAST), morpholino sulphur trifluoride or SOCl2.
The halogenation generally proceeds in a temperature range of from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C., in each case depending on the choice of the halogenating agent and the solvent.
The halogenation generally proceeds at atmospheric pressure; however, it is also possible to carry out the halogenation at elevated or reduced pressure.
The compounds of the general formulae (II) and (M) are novel, and they can be prepared by preparing,
by reaction of the compounds of the general formula (XIV) 
xe2x80x83in which
E is as defined above and
R42 represents C1-C4-alkoxycarbonyl or aryl (D=aryl) with aldehydes of the general formula (XV)
Axe2x80x94CHOxe2x80x83xe2x80x83(XV),
xe2x80x83in which
A is as defined above
and compounds of the general formula (XVI) 
xe2x80x83in which
R43 and R44, together with a carbonyl group, embrace the scope of the meaning of R1 and R2 mentioned above,
the compounds of the general formula (XVII) 
xe2x80x83in which
A, E, R42 R43 and R44 are as defined above
and, in the case of the compounds of the general formula (III), carrying out a reduction, as described above, to furnish the hydroxymethyl function
and, in a last step, converting the alkoxycarbonyl group (R42) by a reduction-oxidation sequence into an aldehyde group.
Solvents which are suitable for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preference is given to methylene chloride.
Suitable oxidizing agents are, for example, cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic alumina, osmium tetroxide and manganese dioxide. Preference is given to sulphur trioxide-pyridine complex in DMSO/methylene chloride and pyridinium chlorochromate on basic alumina.
The oxidizing agent is employed in an amount of from 1 mol to 10 mol, preferably from 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (XVII).
The oxidation generally proceeds in a temperature range of from xe2x88x9250xc2x0 C. to +100xc2x0 C., preferably from 0xc2x0 C. to room temperature.
The oxidation generally proceeds at atmospheric pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.
The compounds of the general formulae (IV), (V), (VII), (XIV), (XV) and (XVI) are known per se or can be prepared by customary methods.
Some of the compounds of the general formulae (VI) and (XV) are known, or they are novel, in which case they can be prepared as described above.
The compounds of the general formulae (IX) and (X) are novel species and can be prepared as described above.
The compounds of the general formula (VIII) are novel and can be prepared by reacting compounds of the general formulae (XVa), (XVIII) and (XIX) 
in which
A, E, R6, R36 and R37 are as defined above
in the presence of an acid.
Suitable solvents for preparing the compounds of the general formula (VIII) are the abovementioned ethers or alcohols. Preference is given to diisopropyl ether.
Suitable acids for preparing the compounds of the general formula (VIII) are, in general, organic carboxylic acids and inorganic acids, such as, for example, oxalic acid, maleic acid, phosphoric acid, fumaric acid and trifluoroacetic acid. Preference is given to trifluoroacetic acid.
The acid is generally employed in an amount of from 0.1 mol to 5 mol, preferably 1 mol, based on I mol of the compounds of the general formula (XIX).
The reaction is generally carried out at atmospheric pressure. However, it is also possible to carry out the reaction at elevated or reduced pressure.
The reaction is generally carried out at the reflux temperature of the solvent in question.
The compounds of the general formulae (XV) and (XIX) are known per se or can be prepared by customary methods.
The compounds of the general formula (XVII) are novel and can be prepared by initially preparing, by reaction of the compounds of the general formula (XX)
Exe2x80x94CO2xe2x80x94R45xe2x80x83xe2x80x83(XX),
in which
E is as defined above and
R45 represents C1-C4-alkyl
with compounds of the general formula (XXI) 
in which
R6 is as defined above
in a solvent in the presence of 18-crown-6 ether, the compounds of the general formula (XXII) 
in which
R6 and E are as defined above,
followed by reaction with ammonium acetate in inert solvents.
Suitable solvents for the first step of the process are the abovementioned ethers and hydrocarbons, preference being given to tetrahydrofuran.
Suitable solvents for the reaction with the compounds of the general formula (XXI) are alcohols, such as, for example, methanol, ethanol, propanol or isopropanol. Preference is given to ethanol.
All steps of the process are carried out at the respective reflux temperature of the solvent in question and at atmospheric pressure.
Some of the compounds of the general formulae (XX) and (XXI) are known, or they can be prepared by known methods.
Some of the compounds of the general formula (XXII) are novel species, and they can be prepared as described above.
The compounds of the general formulae (I) and (Ia) according to the invention have a pharmacological activity spectrum which could not have been foreseen.
The compounds of the general formulae (I) and (Ia) according to the invention have useful pharmacological properties which are superior when compared to the prior art, in particular, they are highly effective inhibitors of the cholesterol ester transfer protein (CETP) and they stimulate the reverse cholesterol transport. The active compounds according to the invention effect a reduction in the LDL cholesterol level in the blood and simultaneously increase the HDL cholesterol level. They can therefore be used for the treatment and prevention of hypolipoproteinaemia, dyslipidaemias, hypertriglyceridaemias, hyperlipidaemias or arteriosclerosis.
The pharmacological activity of the substances according to the invention was determined in the following test:
Preparation of CETP
CETP is obtained in partially purified form from human plasma by differential centrifugation and column chromatography and used for the test. For this purpose, human plasma is adjusted to a density of 1.21 g per ml using NaBr and centrifuged at 50,000 rpm at 4xc2x0 C. for 18 h. The bottom fraction (d greater than 1.21 g/ml) is applied to a Sephadex(copyright)Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 m NaCl/0.001 m TrisHCl pH 7.4 and subsequently eluted using dist. water. The CETP-active fractions are pooled, dialysed against 50 mM Na-acetate pH 4.5 and applied to a CM-Sepharose(copyright) (Pharmacia) column. Elution is subsequently carried out using a linear gradient (0-1 M NaCl). The pooled CETP fractions are dialysed against 10 mM TrisHCl pH 7.4 and subsequently purified further by chromatography over a Mono Q(copyright) column (Pharmacia).
Preparation of radioactively labelled HDL
50 ml of fresh human EDTA plasma are adjusted to a density of 1.12 using NaBr and centrifuged at 4xc2x0 C. in a Ty 65 rotor at 50,000 rpm for 18 h. The upper phase is used to obtain cold LDL. The lower phase is dialysed against 3*41 of PDB buffer (10 mM Tris/HCl pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN3). Per 10 ml volume of retained material, 20 xcexcl of 3H-cholesterol (Dupont NET-725; 1 xcexcC/xcexcl, dissolved in ethanol!) are subsequently added, and the mixture is incubated at 37xc2x0 C. under N2 for 72 h.
The mixture is then adjusted to a density of 1.21 using NaBr and centrifuged in a Ty 65 rotor at 20xc2x0 C. and 50,000 rpm for 18 h. The upper phase is collected and the lipoprotein fractions are purified by gradient centrifugation. To this end, the isolated labelled lipoprotein fraction is adjusted to a density of 1.26 using NaBr. In each case 4 ml of this solution are covered in centrifuge tubes (SW 40 rotor) with 4 ml of a solution of a density of 1.21 and 4.5 ml of a solution of 1.063 (density solutions of PDB buffer and NaBr), and the tubes are subsequently centrifuged in an SW 40 rotor at 38,000 rpm and 20xc2x0 C. for 24 h. The intermediate layer which is found between a density of 1.063 and a density of 1.21 and which contains the labelled HDL is dialysed against 3*100 volume of PDB buffer at 4xc2x0 C.
The retained material contains radioactively labelled 3H-CE-HDL, which is used for the test adjusted to approximately 5xc3x97106 cmp per ml.
To test the CETP activity, the transfer of 3H-cholesterol ester from human HD-lipoproteins to biotinylated LD-lipoproteins is measured.
The reaction is terminated by addition of Streptavidin-SPA(copyright) beads (Amersham) and the transferred radioactivity is directly determined in a liquid scintillation counter.
In the assay mixture, 10 xcexcl of HDL-3H-cholesterol ester (xcx9c50,000 cpm) with 10 xcexcl of Biotin-LDL (Amersham) in 50mM Hepes/0.15m NaCl/0.1% bovine serum albumin/0.05% NaN3 pH 7.4 are incubated with 10 xcexcl of CETP (1 mg/ml) and 3 xcexcl of a solution of the substance to be tested (dissolved in 10% DMSO/1% BSA) at 37xc2x0 C. for 18 h. 200 xcexcl of the SPA streptavidin bead solution (TRKQ 7005) are subsequently added, the mixture is incubated with shaking for another 1 h and subsequently measured in a scintillation counter. The controls used are corresponding incubations with 10 xcexcl of buffer, 10 xcexcl of CETP at 4xc2x0 C. and 10 xcexcl of CETP at 37xc2x0 C.
The activity which is transferred in the control experiments with CETP at 37xc2x0 C. is classified as 100% transfer. The substance concentration at which this transfer is reduced by half is stated as the IC50 value.
In Table A below, the IC50 values (mol/l) for CETP inhibitors are given:
Syrian gold hamsters, which have been bred in our own laboratory, are anaesthetized after 24 hours of fasting (0.8 mg/kg of atropine, 0.8 mg/kg of Ketavet(copyright) s.c., 30xe2x80x2 later 50 mg/kg of Nembutal i.p.). The jugular vein is subsequently exposed and cannulated. The test substance is dissolved in a suitable solvent (usually adalate placebo solution: 60 g of glycerol, 100 ml of H2O, ad 1000 ml PEG400) and administered to the animals via a PE catheter, which is introduced into the jugular vein. The same volume of solvent without test substance is administered to the control animals. The vein is subsequently tied off and the wound is closed.
The test substances can also be administered p.o. by dissolving the substances in DMSO and suspending them in 0.5% tylose and administering them perorally using a pharyngeal tube. Identical volumes of solvent without test substance are administered to the control animals.
At different intervalsxe2x80x94up to 24 hours after administrationxe2x80x94blood samples are taken from the animals by puncture of the retro-orbital venous plexus (approximately 250 xcexcl). Coagulation is completed by incubation at 4xc2x0 C. overnight, and the samples are subsequently centrifuged at 6000xc3x97g for 10 minutes. The CETP activity is determined in the resulting serum using the modified CETP test. The transfer of 3H-cholesterol ester from HD-lipoproteins to biotinylated LD-lipoproteins is measured as described above for the CETP test.
The reaction is terminated by addition of Streptavidin-SPAR beads (Amersham), and the transferred radioactivity is directly determined in a liquid scintillation counter.
The test protocol is carried out as described under xe2x80x9cCETP testxe2x80x9d. However, to test the serum, only 10 xcexcl of CETP are replaced by 10 xcexcl of the appropriate serum samples. Corresponding incubations of sera of untreated animals serve as controls.
The activity that is transferred in the control experiments using control sera is classified as 100% transfer. The substance concentration at which this transfer is reduced by half is stated as the ED50 value.
In experiments for determining the oral activity on lipoproteins and triglycerides, test substance, dissolved in DMSO and suspended in 0.5% tylose, is administered perorally by means of a pharyngeal tube to Syrian gold hamsters which have been bred in our own laboratory. To determine the CETP activity, blood samples (approximately 250 xcexcl) are taken by retro-orbital puncture prior to the start of the experiment. The test substances are subsequently administered perorally using a pharyngeal tube. Identical volumes of solvent without test substance are administered to the control animals. Subsequently, the animals have to fast and at different intervalsxe2x80x94up to 24 hours after administration of the substancesxe2x80x94blood samples are taken by puncture of the retro-orbital venous plexus.
Coagulation is completed by incubation at 4xc2x0 C. overnight, and the samples are subsequently centrifuged at 6000xc3x97g for 10 minutes. The content of cholesterol and triglycerides in the resulting serum is determined using modified commercially available enzyme tests (cholesterol enzymatic 14366 Merck, triglycerides 14364 Merck). Serum is diluted in a suitable manner with normal saline solution.
100 xcexcl of serum dilution and 100 xcexcl of test substance are transferred into 96-well plates and incubated at room temperature for 10 minutes. The optical density is subsequently determined at a wavelength of 492 nm using an automatic plate reader. The triglyceride and cholesterol concentrations of the samples are determined with the aid of a standard curve measured in parallel.
The determination of the HDL-cholesterol content is carried out after precipitation of the ApoB-containing lipoproteins using a reagent mixture (Sigma 352-4 HDL cholesterol reagent) in accordance with the instructions of the manufacturer.
The substances to be tested were administered to transgenic mice, which were bred in our own laboratory (Dinchuck, Hart, Gonzalez, Karmnann, Schmidt, Wirak; BBA (1995), 1295, 301), via the feed. Prior to the beginning of the experiment, blood samples were taken retro-orbitally from the mice to determine cholesterol and triglycerides in the serum. The serum was obtained as described above for hamsters by incubation at 4xc2x0 C. overnight and subsequent centrifugation at 6000xc3x97g. After one week, blood samples were again taken from the mice to determine lipoproteins and triglycerides. The change of the measured parameters are expressed as a change in per cent based on the initial value.
The invention furthermore relates to the combination of hetero-tetrahydroquinolines of the general formula (I) with a glucosidase and/or amylase inhibitor for the treatment of familial hyperlipidaemias, of obesity (adipositas) and of diabetes mellitus. Glucosidase and/or amylase inhibitors in the context of the present invention are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, trestatin, pradimicin-Q and salbostatin.
Preference is given to the combination of acarbose, miglitol, emiglitate or voglibose with one of the abovementioned compounds of the general formula (I) according to the invention.
Furthermore, the compounds according to the invention can be combined with cholesterol-lowering vastatines or ApoB-lowering principles, in order to treat dyslipidaemias, combined hyperlipidaemias, hypercholesterolaemias or hypertriglyceridaemias.
The abovementioned combinations can also be used for primary or secondary prevention of coronary heart diseases (for example myocardial infarction).
Vastatines in the context of the present invention are, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. ApoB-lowering agents are, for example, MTP inhibitors.
Preference is given to the combination of cerivastatin or ApoB inhibitors with one of the abovementioned compounds of the general formula (I) according to the invention.
The novel active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. In this case the therapeutically active compound should in each case be present in a concentration of from approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds using solvents and/or carriers, if appropriate using emulsifiers and/or dispersants, it optionally being possible, for example, to use organic solvents as auxiliary solvents if the diluent used is water.
Administration is carried out in a customary manner, intravenously, orally, parenterally or perlingually, in particular orally.
In the case of parenteral administration, solutions of the active compound can be used by employing suitable liquid carrier materials.
In general, it has proved advantageous, in the case of intravenous administration, to administer amounts of from approximately 0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg, of body weight to achieve effective results, and in the case of oral administration the dosage is approximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg, of body weight.
In spite of this, if appropriate it may be necessary to depart from the amounts mentioned, namely depending on the body weight or on the type of administration route, on the individual reaction towards the medicament, the manner of its formulation and the time at or interval during which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned has to be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day
Cy=Cyclohexane
EA=Ethyl acetate
PE=Petroleum ether
THF=Tetrahydrofuran
DAST=Dimethylaminosulphur trifluoride
PTA=para-toluenesulphonic acid
PDC=Pyridinium dichromate
PE/EA=Petroleum ether/ethyl acetate
Tol=Toluene
2-Cyclopentyl-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenzoyl)-1,4,5,6,7,8-hexahydro-quinolin-5-one 
1.425 g (5.03 mol) of 3-amino-3-cyclopentyl-1-(4-trifluoromethylphenyl)-propenone are suspended in 25 ml of diisopropyl ether. 740 mg (5.28 mol) of dimedone, 0.39 ml (5.03 mol) of trifluoroacetic acid and then 592 mg (5.28 mol) of thiophen-3-aldehyde are added. The mixture is heated at reflux for 2 hours, which immediately gives a yellow solution from which, after 30 minutes, product precipitates out. The mixture is cooled and the product is filtered off with suction and washed with diisopropyl ether. The product is recrystallized from acetonitrile.
Yield: 741 mg, m.p. 228-229xc2x0 C.
The mother liquor gives another 230 mg of pure product.
The compounds listed in Table I are prepared analogously to the procedure of Example I: